tbuckley/cabot-search huggingface dataset:
DDDR-35. TARGETING GBM INVASION BY INHIBITING KCNA1 WITH 4-AMINOPYRIDINE: AN FDA APPROVED DRUG THAT EASILY PASS THROUGH THE BBB
Authors: Sophie Xiao, Lin Li, Deying Yang, Huiyuan Zhang, Yulun Huang, Wan-Yee Teo, Akash Patel, Yuchen Du, Xiao-Nan Li
Journal: Neuro-Oncology (2022)

Abstract Diffuse invasion is a hall mark of glioblastoma (GB) and one of the primary causes of poor clinical outcomes in GBM patients. Tumor cells migrate deep into the normal brain tissues are frequently protected by the BBB, making them particularly difficult to treat. New therapeutic targets are needed. Our previous studies using spatially dissected and functionally validated matching pairs of invasive and tumor core GBM cells identified KCNA1 as a shared gene that is selectively over-expressed in the invasive GBM cells in 6 patient derived orthotopic xenograft (PDOX) mouse models of pediatric GBM (Huang YL et al, Adv Science 2021). A subsequent analysis of adult GBM RNAseq data from IVY Atlas revealed a significantly elevated expression of KCNA1 (4.9 fold) in the invasive edges of patient GBM tumors. It is also one of the 11 core molecules identified in GEO and TCGA databases through an integrated bioinformatic analysis (Yang J, Front Onc 2021). To determine the anti-invasive activities of targeting KCNA1, we treated three highly invasive adult GBM PDOX models with 4-aminopyridine (4-AP), an old lipid soluble drug that easily penetrate the BBB, at 5 mg/kg, i.p., 5 days/week for 8 weeks acing alone or in combination with fractionated radiation (at 2 Gy/day x days). As single agent, 4-AP significantly extended median animal survival times in 1/3 GBM models (69 to 77 days, P = 0.033). Combination with XRT did not significantly improve the animal survival times in the three models. Systematic analysis of GBM invasion in mouse brains of the 3 PDOX models before, during and after 4-AP treatment revealed remarkable inhibition of tumor invasion. Our data highlighted the role of KCNA1 in promoting GBM invasion and support the fine tuning of 4-AP dose, schedule, and length of treatment to serve as a novel component of anti-GBM invasion therapies.
NIMG-03. PREOPERATIVE DEXAMETHASONE LEADS TO SIGNIFICANT REDUCTIONS IN PERITUMORAL EDEMA FOR PATIENTS WITH BRAIN METASTASES
Authors: Hao Tan, Stephen Bowden, Barry Cheaney, Emma Richie, Charles de Leeuw, Matthew Wood, Ahmed Raslan, Seunggu Han, Ramon Barajas
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Corticosteroids are commonly used preoperatively in patients with brain metastases to mitigate symptoms related to vasogenic peritumoral edema (PTE). Though these tumors are highly prevalent, surprisingly few studies have examined the effect of steroids on PTE evident on MRI. We investigated whether steroid administration was associated with greater reduction in PTE in brain metastasis patients compared to steroid-naïve patients. Additionally, we sought to determine if PTE reductions reflect preoperative neurologic improvement and whether an association existed between change in PTE and preoperative steroid dosing. METHODS We identified 27 patients with brain metastases and two pre-operative MRIs—one pre- and one post-steroid administration. PTE and tumor volume was calculated from FLAIR or T2 sequences using 3D Slicer. PTE was quantified with Edema Index (EI). Pertinent demographic, clinical, and dexamethasone dosing data were extracted from patient charts. Descriptive statistics were performed to compare demographic, clinical, and radiographic data between patient strata. A Pearson's R correlation was performed to assess for an association between percent change in PTE and dexamethasone dosing. All statistics were computed in R with a threshold of α= 0.05. RESULTS Patients that received preoperative dexamethasone demonstrated significantly greater percent reduction in PTE compared to their steroid naïve counterparts (p = 0.02). This finding was despite similar time elapsed between MRI studies across both groups. Similar PTE changes were observed in those with and without preoperative neurologic improvement. No significant correlation was found between percent-change in PTE and dexamethasone dosing. CONCLUSIONS We are the first to demonstrate that preoperative dexamethasone administration significantly reduces PTE in patients with brain metastases when compared to a steroid naïve reference group. Curiously, a superior reduction in PTE was not reflective of neurologic improvement. The clinical significance of this merits further study.
QLTI-07. IDENTIFYING RISK FACTORS FOR PROLONGED TRANSFUSION-DEPENDENT TEMOZOLOMIDE-INDUCED THROMBOCYTOPAENIA IN PATIENTS RECEIVING CONCURRENT CHEMO-RADIOTHERAPY FOR GLIOBLASTOMA (GBM)
Authors: Nashwah Ismail, Karan Patel, Tapan Parikh, Rovel Colaco, Catherine McBain
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Temozolomide-induced thrombocytopaenia is a well-recognised clinical issue with significant inter-patient variation. However, knowledge of the extent of the problem and its potential risk factors remains limited. Our aim was to determine the incidence of patients requiring platelet transfusion and ascertain associated risk factors using real-world data. METHODS Data from patients with GBM receiving concurrent temozolomide-chemo-radiotherapy (CRT) from 01/01/18-31/12/2019 retrospectively reviewed. Patients receiving platelet transfusion identified (Local policy: transfusion for platelet count ≤ 30x109/L). Logistic regression and chi-squared tests used to compare variables in patients requiring platelet transfusion and those not. RESULTS 111 patients with GBM received TMZ-CRT (60Gy/30#; 75mg/m2 temozolomide). 12/111 patients received platelet transfusion: 10 during concurrent-CRT and 2 during adjuvant-treatment. Numbers of transfusions: 1-2: 7 patients; 3-4: 2 patients; ≥ 5 transfusions: 3 patients. Median time from platelet count ≥ G3 to ≥ 100 in 11/12 patients: 38 days (range 6-72). 1 did not recover, patient died 84 days following start of TMZ-CRT with thrombocytopaenia. Comparison of the transfused vs the non-transfused cohort shows: transfused: 50% female; non-transfused: 36% female. Mean BSA: transfused: 1.73, SD0.21; non-transfused:1.96, SD0.22 (OR 0.01; 95% CI:0.0003 – 0.16). Mean age: transfused: 57, SD15.8; non-transfused: 58, SD10.7 . Mean baseline platelet count: transfused: 329, SD185; non-transfused: 319, SD117. Mean PTV: transfused: 400, SD115; non-transfused: 414, SD123. There were no statistically significant associations with demographics, age, blood parameters or planning target volume. CONCLUSION This study demonstrates a subset of patients who experience severe and prolonged thrombocytopaenia. Risk factors elucidated are female sex and lower BSA. Large-scale prospective trials evaluating a panel of predictors including concomitant medications, patient MGMT variants and temozolomide-metabolite concentrations would be valuable. Precise stratification of this vulnerable subgroup may permit consideration of temozolomide dose-capping in the future. Careful informed consent with all patients and caution with intensifying treatment under trials is vital presently.
PATH-23. HIGHLY INFILTRATING OLIGODENDROGLIOMAS SHOW DIFFERENT MORPHOLOGY FROM TYPICAL OLIGODENDROGLIOMAS WHILE MAINTAINING GOOD RESPONSE TO CHEMO-RADIATION THERAPY
Authors: Fumi Higuchi, Takeo Uzuka, Takuma Sumi, Hazuki Matsuda, Kayoko Iwata, Masahiro Shin, Keisuke Ueki, Hiroyoshi Akutsu
Journal: Neuro-Oncology (2022)

Abstract Oligodendrogliomas are diffuse gliomas located in the cerebral hemisphere, and the MRI typically show swollen cortex and subcortical white matter by the tumor cells. IDH mutation and 1p/19q co-deletion define oligodendrogliomas in WHO classification, and these genetic alterations are associated with good response to chemo-radiation therapy and better prognosis compared to the IDH-mutant astrocytomas. We reviewed MRI findings of 60 oligodendrogliomas with 1p/19q co-deleted tumors which were diagnosed at Dokkyo Medical University since 1999. Of those, 3 cases showed highly infiltrating pattern in which tumors were more predominant in the white matter than the cortex and the infiltration involved multiple lobes. We retrospectively investigated those 3 cases for histological features, treatment, and clinical outcome. There were 2 males and 1 female. MRI showed faint-brushed Gd enhancement around the center of the tumor-infiltrated area in 1 case, while there was no enhancing lesion in other 2 cases. All three underwent stereotactic biopsy. Histologically, all 3 cases lacked typical oligodendroglioma morphology: the tumor cells have irregular round, oval to elongated nuclei without perinuclear halo and had dense, closed chromatin similar to astrocytoma. Two cases underwent chemotherapy (TMZ and PAV accordingly), without radiation and 1 case underwent chemotherapy with radiation as the primary treatment. Interestingly, all three tumors responded well not only to the primary treatments but also to the radiation therapy administered after recurrence, although all eventually succumbed to the tumor. PFS were 16, 37, 67 months and OS were 104, 70, 115 months for each, which were at the worse end as oligodendrogliomas but are apparently better than astrocytomas. Highly infiltrating oligodendrogliomas appeared to show significantly different MRI and histological features from typical oligodendrogliomas that primarily involve cerebral cortex. The underlying mechanism of such differences might involve specific genetic alterations and/or gene expression alterations that may not affect treatment response.
BIOM-47. PREDICTORS OF SEIZURE AT ONSET USING A FUNCTIONAL VARIANT ANALYSIS OF TARGETED NEXT GENERATION SEQUENCING IN GBM
Authors: Mary Jane Lim-Fat, Rifaquat Rahman, Bryan Iorgulescu, Varun Bhave, Gilbert Youssef, Marie Allen, Ugonma Chukwueke, J Ricardo McFaline-Figueroa, Lakshmi Nayak, Eudocia Lee, David A Reardon, Tracy Batchelor, Rameen Beroukhim, Raymond Huang, Wenya Linda Bi, Keith Ligon, Patrick Y Wen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Adverse events (AE) including seizures cause significant morbidity in patients with GBM. We propose a novel method for assessing genomic predictors of AEs using results from a clinical targeted sequencing platform with variant function analysis. METHODS We identified 1,011 consecutive adult patients with newly diagnosed, histologically confirmed IDH-wildtype GBM with targeted exome NGS (Oncopanel) at Dana-Farber Cancer Institute from 2013-2019. Seizure at presentation was retrospectively identified as an AE. Biologic function (high loss, low loss, neutral, low gain and high gain) was assigned to variants using a three-tiered approach leveraging a genetic variant database (OncoKB), followed by analysis using protein prediction tools (Sift, Polyphen2 and Provean). Univariate logistic regression was performed for each relevant altered gene against the outcome of interest with false-discovery rate correction. Genes associated with seizure at presentation were included iteratively in a multivariate logistic model including other predictors of the outcome. RESULTS Our analysis included 470 GBM patients with 107 genes and 12 whole chromosome or arm level candidate variants covered by all versions of Oncopanel and with &amp;gt;10% alteration. Seizure at presentation occurred in 143/463 patients (31%) and was associated with EGFR amplification (high gain) (OR: 2.76, 95% CI: 1.4-5.3, p = 0.04). In a multivariate analysis (including age, sex, and preoperative tumor volume), EGFR amplification remained statistically significant (OR: 1.5, 95% CI: 1.0-2.2, p = 0.03). CONCLUSION Genomic biomarkers based on functional variant analysis of a routine clinical panel may predict adverse events in GBM. Seizure at presentation was independently associated with EGFR amplification. Our ongoing analysis will look at predictors of myelosuppression, thromboembolism, pseudoprogression and early progression using a similar approach. Identifying molecular risk factors could improve the management of patients through supportive care and consideration of prophylactic therapies.
EPCO-19. ADAPTIVE RESPONSES TO GENOME-WIDE DNA DAMAGE RESULT IN TOPOLOGIC GENOME REORGANIZATION IN GLIOBLASTOMA
Authors: Aram Modrek, Catherine Do, Zeyan Zhang, Yingwen Deng, Jerome Karp, Ravesanker Ezhilarasan, Belen Valor, Giulia Cova, Matiar Jafari, Matija Snuderl, Aristotelis Tsirigos, Jane Skok, Erik Sulman
Journal: Neuro-Oncology (2022)

Abstract In glioblastoma, treatment with radiation and chemotherapy leads to DNA-damage and most DNA breaks are faithfully repaired, but the impact on the epigenome is largely unknown. Using newly developed tools to enable these studies, we hypothesize that genome-wide DNA damage leads to local alterations in DNA-methylation, genome organization, and results in persistent gene-expression alterations near sites of repaired damage. We use patient-derived human glioblastoma stem-like cells (GSCs) as a model. DNA breaks are induced using (i) irradiation or (ii) a novel “multi-cut” CRISPR-Cas9 DNA break system followed by multi-omic profiling. With radiation, we find significant and wide-spread alterations in DNA-methylation after treating multiple glioblastoma cultures. However, it is challenging to study local alterations around sites of radiation induced damage because breaks are introduced at different sites in each cell, resulting in stochastic DNA methylation alterations. To circumvent this issue, we developed a multi-cut CRISPR-Cas9 DNA break system that targets 142 or 483 pre-defined loci. Induction of pre-mapped genome-wide cuts reproduces a similar level of toxicity as standard doses of radiation. To assess repair efficiency and confirm induction of breaks, we performed targeted sequencing of the 142 or 483 sites to allow for high coverage sequencing. To understand how DNA damage may lead to regional epigenetic and 3D chromatin organization changes, we performed HiC, Methylation-seq, ChIP-seq of the chromatin organizing factor CTCF and enhancer marker H3K27ac, as well as RNA-seq, before and after cut induction. Our findings show significant mega-base scale alterations in chromatin contacts centered around cut sites, enrichment of DNA methylation alterations at regulatory elements and altered gene-expression. The findings here provide a mechanistic view of the interplay between genome-wide DNA damage, DNA methylation and genome re-organization, and have wide ranging implications for the effect of DNA damage on the epigenome in glioblastoma.
TMIC-27. SPATIALLY RESOLVED T CELL RECEPTOR SEQUENCING (SPTCR-SEQ) UNCOVERS REGIONAL DIVERSITY OF ANTI-TUMOR IMMUNE RESPONSES
Authors: Jasim Kada Benotmane, Jan Kueckelhaus, Juergen Beck, Oliver Schnell, Dieter Henrik Heiland
Journal: Neuro-Oncology (2022)

Abstract Regional diversity of anti-tumor immunity in glioblastoma (GBM) has been poorly investigated due to technical limitations. To overcome these hurdles, we developed SPTCR-seq (SPatial TCell Receptor sequencing) to spatially profile T cell immune response. Here, we performed 10X-Visium spatial transcriptomics and SPTCR-seq on 9 de-novo IDH wt glioblastoma. For SPTCR-seq, we captured enriched T-cell receptor (TCR) sequences by hybridization followed by Oxford nanopore (ONT) long-read sequencing. We established a computational pipeline for spatial demultiplexing, error correction and TCR reconstruction using a Seq2Vector model, followed by a long-term memory autoencoder to deconvolute and compare CDR3 sequence similarities across patients. The on-target rate for detected TCR genes reached over 85%, of which our long-TCR algorithm could completely reconstruct TCRs in over 70%. To decipher the regional diversity of T-cell clonality, we performed spatially weighted regression to estimate the overlap of T-cell clonal expansion to the recently described regional transcriptional niches. We found that myeloid cell infiltration was highly correlated with increased T cell diversity. We integrated single cell RNA-seq data and annotated T cell subtypes through the “natural barcode” of the CDR3 sequence, revealing that CD4+ T cells interact with myeloid cells via MHCII in segregated areas, also described as the Reactive Immune niche. In contrast, CD8+ T cells exhibit a dysfunctional/exhausted phenotype at the same location. In comparison to the myeloid-infiltrated regions, the hypoxia-associated niches showed increased CD8+ T cells with greater clonal expansion, suggesting an immune response anti-cancer immunity. Global spatial vector field analysis revealed a spatial co-occurrence of metabolic vulnerability and a mutational burden with CD8+ T effector cells negatively associated with myeloid cell infiltration. Integration of CDR3 sequences in different patients revealed higher similarity of motifs of CD4+ compared with CD8+ T cells in hypoxia areas. Our data provide new insights into the regional heterogeneity of cancer immunity.
INNV-30. RETROSPECTIVE ANALYSIS OF TTFIELDS IN PATIENTS WITH HGG BASED ON THE CRITERIA OF 2021 WHO CNS5
Authors: Xiaoyan Yang, Li Zhang, Yanming Ren, Qing Mao, Yanhui Liu, Xiang Wang, Ni Chen, Qiang Yue, Xin Wu, Lei Liu, Feng Wang
Journal: Neuro-Oncology (2022)

Abstract PURPOSE High-grade glioblastoma (HGG) was highly malignant and had a poor prognosis, with an overall median survival time of only 15 months. Tumor-Treating Fields (TTFields) has been approved for the newly diagnosed glioblastoma (GBM), and more clinical evidence is needed for its use in HGG. The aim of this study was to analyze the efficacy and safety of TTFields in patients with HGG in our center. METHODS We analyzed baseline characteristics, efficacy, and safety data of 27 newly diagnosed HGG patients treated with TTFields for at least four weeks from January 2020 to February 2022 at West China Hospital of Sichuan University. All the pathological grades were diagnosed based on the 2021 World Health Organization Classification of Tumors of the Central Nervous System (2021 WHO CNS5) criteria. RESULTS Twenty-one patients (77.78%) were diagnosed as grade 4. Among them, the percentage of gross total resection was 81.48%, and MGMT promoter methylation was 51.85%. The median interval from surgery to TTFields initiation of treatment was 2.47 months (95% CI, 1.47-10.37). The median follow-up time was 12.47 months (95% CI, 8.6-15.03). The 12-month PFS rate and 12-month OS rate were 70.73% and 90.24%, respectively. Median PFS and OS have not been reached. The median compliance of patients wearing TTFields was as high as 95%, and their associated adverse events were patch-induced rash and ulcers, all of which were grade 1 ~ 2. CONCLUSIONS This study is the first to define HGG patients with the 2021WHO CNS5. TTFields were observed in this retrospective analysis to improve patients’ 12-month PFS rate and OS rate. Adherence was much higher than that reported in clinical studies, and safety remained good. More extended Survival data would be updated by further follow-up.
BIOM-18. CLINICOGENOMIC PREDICTORS FOR THE PATTERN OF FAILURE IN HIGH-GRADE GLIOMA
Authors: Byung-Hee Kang, Joo Ho Lee, Tae Min Kim, Hongseok Yun, Jae-Kyung Won, Seung Hong Choi, Soon-Tae Lee, Sung-Hye Park, Chul-Kee Park
Journal: Neuro-Oncology (2022)

Abstract Background High-grade gliomas, the most common primary brain tumors, are highly lethal and treatment options remain limited. Despite advances in genomic technologies, there are few molecular biomarkers to guide precision medicine for high-grade glioma. Here, we aimed to identify the clinicogenomic features associated with its prognosis and recurrence patterns. MATERIALS/METHODS Our single-institution retrospective analysis included 182 patients diagnosed with high-grade gliomas who underwent next-generation sequencing targeting 82 brain tumor-relevant genes. Clinicopathological status, treatment characteristics, survival, and genomic profiles were analyzed. RESULTS At a median follow-up of 23 months (range, 2-229 months), 151 patients (83%) had progression or recurrences. Local and distant recurrences were observed in 132 (72.5%) and 101 (54.9%) patients, respectively. The most common genomic variants in high-grade gliomas were TP53 (42.9%), IDH1/2 (23.1%), TERT promoter (38.5%), ATRX (13.2%), H3F3A (7.1%), and SETD2 (6.0%) mutation. Regarding copy number variants, amplification of EGFR (20.9%), PDGFRA (9.9%), MYCN (2.2%) and loss of CDKN2A/2B (49.5%), PTEN (37.9%), RB1 (17.6%), and 1p19q codeletion(9.3%) were the most common copy number aberrations. On multivariate cox regression anlalysis, MYCN amplification (HR 6.08 95% CI 1.91-19.35, p = 0.002), and SETD2 mutation (HR 0.19 95% CI 0.06-0.62, p =0.06) were independent predictors of overall survival, in relation to previously established prognostic factors including age, Eastern Cooperative Oncology Group Performance Status (ECOG PS) scale, extent of resection, MGMT promoter methylation, and IDH1/2 mutation. Interestingly, MYCN amplification (HR 5.24 95% CI 1.69-16.27, p = 0.004), SETD2 mutation (HR 0.35 95% CI 0.12-0.99, p =0.048) were independent predictors of failure from distant recurrences. CONCLUSION The assessment of genomic characteristics in conjunction with pattern of failure for high-grade glioma aids to identify patients who are likely to benefit from personalized medicine. We identified SETD2 mutation, and MYCN as a prognostic biomarkers with potential therapeutic implications in patients with high-grade glioma.
RTID-05. TRIAL IN PROGRESS: DOSE-FINDING STUDY AND EVALUATION OF [177LU]LU-DOTA-TATE IN COMBINATION WITH STANDARD OF CARE IN NEWLY DIAGNOSED GLIOBLASTOMA AND AS A SINGLE AGENT IN RECURRENT GLIOBLASTOMA
Authors: Patrick Y Wen, Timothy Cloughesy, Arnaud Demange, Ken Herrmann, Michael Weller, Evren Zor
Journal: Neuro-Oncology (2022)

Abstract Patients with glioblastoma have a poor prognosis despite extensive efforts to develop new treatments. Standard of care for newly diagnosed patients is surgery followed by radiotherapy plus temozolomide. However, temozolomide only provides a clinical benefit to patients who have glioblastomas with a methylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promotor. Disease recurrence is inevitable and subsequent treatments have poor outcomes due to limited efficacy and a lack of established therapeutic regimens. [68Ga]Ga-DOTA-TATE is a radioligand imaging agent that selectively binds to somatostatin receptors (SSTRs) and is used with positron emission tomography (PET) for the molecular imaging of SSTR-positive neuroendocrine tumors. Glioblastoma tumoral PET scans have shown moderate uptake of [68Ga]Ga-DOTA-TATE. The radioligand therapy [177Lu]Lu-DOTA-TATE has the same SSTR-targeted ligand and demonstrated promising clinical activity in a pilot study in patients with Grade III/IV gliomas. This Phase 1b open-label dose-finding study (NCT05109728) will determine the recommended [177Lu]Lu-DOTA-TATE dose in three different groups of glioblastoma (newly diagnosed with methylated MGMT promoter [group 1], newly diagnosed with unmethylated MGMT promoter [group 2], and recurrent disease [group 3]). All participants will be scanned with [68Ga]Ga-DOTA-TATE imaging during screening and, for each group, approximately 15 participants will be enrolled in consecutive cohorts of 3–6 participants. All participants will receive up to 6 administrations of [177Lu]Lu-DOTA-TATE (initial dose 150 mCi with 3 provisional dose levels up to 250 mCi) using the Bayesian Optimal Interval design. Group 1 will receive [177Lu]Lu-DOTA-TATE every 4 weeks with concomitant radiotherapy and temozolomide, followed by temozolomide maintenance. Group 2 will receive [177Lu]Lu-DOTA-TATE every 4 weeks for 3 doses with radiotherapy then every 3 weeks as a single agent. Group 3 will receive [177Lu]Lu-DOTA-TATE only, every 3 weeks. The primary endpoint is incidence of dose limiting toxicity. Secondary endpoints include overall objective status (modified RANO criteria), progression free survival, overall survival and safety.